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Carcinogenicity

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Description of key information

The observed  increased incidence of thyroid follicular adenoma/cystadenoma is considered to be a secondary effect due to liver effects

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
15.3 mg/kg bw/day

Additional information

TMQ was investigated in a comprehensive chronic 2 years oral feeding study in rats with 60 animals/sex/group. Concerning non-neoplastic endpoints see chapter repeated dose toxicity. In addition to the systemic effects an increased incidence of thyroid follicular adenoma/cystadenoma was reported. The increased incidence was statistically significant only in females in the high dose group. The incidences are as follows: males: control: 5/60, low dose group: 2/60 mid dose group: 4/60 high dose group: 10/60; females: control 1/60; low: 3/58, mid: 0/60, high: 9/59*.

Additional lesions observed were considered to occur spontaneously and, due to the lack of a dose response relationship and/or lack of consistency in the incidences across the various death categories in this study, were not considered related to administration of the test material.

In addition a cellular proliferation assay was performed with liver tissue. A slightly, but statistically significantly, increase in hepathic cell proliferation was reported in the high dose females after 4 days of exposure. The toxicological significance, if any, of this difference is not known. There were no significant differences in females at the other time points investigated (1 and 5 months). There were no differences in cell proliferation in male livers at any time point.

Tumors of thyroid gland follicular cells are fairly common in chronic studies of chemicals in rodents. Experimental evidence indicates that one mode of action for rodent thyroid tumors involves disruption of thyroid-pituitary functioning. Circulating thyroid hormone determines the level of operation of most cells of the body, too much or too little hormone results in disease. Control of the concentration of this endocrine hormone in the blood is regulated mainly by a negative feedback involving different organs: the thyroid gland, which produces thyroid hormone, the pituitary gland and hypothalamus, which respond to and help maintain optimal levels of thyroid hormone and the liver which metabolizes thyroid hormone, largely by conjugation reactions, to excrete it into the bile. There is an association between thyroid tumors and liver toxicity in rodent cancer studies (McConnell. 1992. Regul Toxicol Pharmacol 16:177-188.; Haseman and Lockhart. 1993. Environ Health Perspect 101:50-54). Certain chemicals induce liver microsomal enzymes and enhance thyroid hormone metabolism and removal. Another common mechanism is microsomal induction due to enlargement of hepatocytes in the centrilobular region (EPA/630/R-97/002 March 1998; R N Hill,1998, Environ Health Perspect. 1998 August; 106(8): 447–457).

Increased liver weight and enlargement of hepatocytes in the centrolobular region is observed in the chronic TMQ study. Absolute liver weights were increased in high dose males and females; liver weight relative to brain weight was increased in mid dose females; there were no other organ weights attributed to administration of the test material. Histopathologic evaluations of the liver indicated to following effects in the high dose animals: bile duct proliferation / cholangiofibrosis. (males: controls 31/60; high dose males 43/60*), focus of cellular alteration (males: 17/60; 30/60*), hepathocellular hypertrophy centrilobular (males: 1/60, 13/60*; females: 0/60; 11/60*), hepathocellular vacuolisation centrilobular (females: 1/60; 16/60*), sinus dilatation (females: controls 2/60; mid dose 10/59*; high dose 17/60*).

Based on the above mentioned mechanistic considerations and the observed liver effects in the 2 years study, it is likely that the observed effects on the thyroid are secondary and due to due to liver effects.


Carcinogenicity: via oral route (target organ): glandular: thyroids

Justification for classification or non-classification

Based on the available information no classification is required according to the EU classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).